1. Field of the Invention
The present invention relates generally to the fields of protein chemistry, molecular biology, pharmaceutical compositions, and therapeutics. More particularly, the invention concerns methods, compositions concerning urocortin-2 analogs, and nucleic acids encoding urocortin-2 analogs.
2. Description of Related Art
Corticotropin-releasing factor (CRF) is a 41-amino acid peptide best known for its indispensable role in initiating pituitary-adrenal responses to stress, an effect mediated by type 1 CRF receptors. In addition, corticotropin-releasing factor is widely distributed in brain, and participates in the mobilization of complementary autonomic and behavioral adjustments to a variety of threatening circumstances. Corticotropin releasing factor and its related family of peptides play important roles in regulation of the hypothalamic-pituitary-adrenal axis (HPA) under basal and stress conditions. It is also believed that corticotropin-releasing factor is also involved in other neuroendocrine and paracrine responses in many tissues. Members of the CRF family integrate endocrine, autonomic and behavioral responses to stressors. These peptides may also be implicated in the control of appetite, arousal, and cognitive functions. Severe psychological and physiological consequences can occur as a result of the long term effects of stress, such as anxiety disorders, anorexia nervosa and melancholic depression.
Corticotropin-releasing factor family members mediate their biological actions by specifically binding to CRF receptors with high affinities. CRF receptors are G-protein coupled receptors that act through adenylate cyclase and are structurally related to the secretin family. This family also includes GRF, VIP, PTH, and the Calcitonin receptor. CRF-R1 receptor is distributed throughout the brain and is found in sensory and motor relay sites. The CRF-R2α is distributed in lateral septum, ventral medial hypothalamus, nucleus of the solitary tract and the dorsal raphe nucleus, which are areas where CRF-R1 is expressed very little or not at all. The CRF-R2β is found mostly in peripheral sites including the heart, blood vessels, gastrointestinal tract, epididymis, lung and skin. The pharmacology of the two types of receptors differs in that corticotropin-releasing factor has a low affinity for CRF-R2 but a high affinity for CRF-R1. Other related peptides such as carp urotensin, frog sauvagine, and urocortin have a high affinity for CRF-R2. CRF-R2 knockout mice demonstrate an increased anxiety-like behavior caused by hypersensitivity to stressors.
A mammalian CRF-related neuropeptide, urocortin (Ucn), binds with high affinity to both known CRF receptor types, whereas CRF is bound in a highly preferential manner by CRF-R1. Centrally administered urocortin is more potent than CRF in suppressing appetite but less so in generating acute anxiety-like effects and generalized behavioral activation. This has been taken to indicate that urocortin might mediate some stress-related effects attributed initially to CRF, at least in part by serving as an endogenous ligand for CRF-R2. Urocortin has been proposed as a therapeutic agent in heart disease (see, e.g., Raddino et al., 2007; Davidson et al., 2009).
Urocortin 2 (Ucn 2), one of the CRF peptide family members, is thought to be an endogenous ligand for CRF type 2 receptor (CRF-R2). The roles of urocortin 2 in the body are diverse, and include involvement in affective disorders, stimulation of the immune system, and cardioprotection (Lawrence and Latchman, 2006). Therapeutic application of urocortin 2 is limited because of the limited water solubility of the urocortin 2 peptide. Therefore, there is the need for active urocortin 2 analogs that have improved water solubility.